Polymer nanoparticles (NPs) play an important role in drug delivery and are particularly useful for delivery of chemotherapy drugs. For clinical applications, the control of nanoparticle size and surface morphology are important. Other aspects of the design of particulate systems can also be important for the use of nanoparticles as delivery systems in vivo. It is preferred that drug loading in the polymeric nanoparticle is reasonable high for improved efficacy. This is particularly important for enhanced effectiveness of nanoparticles in cancer therapy 1-3 
High drug loading4,5 decreases manufacturing cost and increases patient compliance by reducing the dose needed for each administration. In addition, drug molecules in nanoparticle delivery vehicles preferably remain substantially encapsulated in the polymeric nanoparticles on administration to a patient to be released in a sustained manner over time or after they accumulate at a desired location. More specifically for nanoparticle applications to cancer therapy, it is important that anticancer agents remain encapsulated with little or no drug release while in the vasculature and release the anticancer agent only after the nanoparticles extravasate to tumor tissues.
Well-controlled drug release has been realized only in a limited number of drug delivery systems, most of which are liposomes.6 Currently, there are about 10 liposomal delivery vehicles approved for clinical applications of which only one, Abraxane, an albumin bound paclitaxel nanoparticle with size ˜130 nm, is a polymeric nanoparticulate delivery vehicle.6,7 Abraxane,8,9 appears to contain a large quantity of lipids on the surface of albumin nanoparticles which gives them liposome-like properties in regulating drug release. To date no polyester based nanoencapsulates are approved for clinical cancer treatment.
In a recent study using poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-PLGA) to nanoencapsulate docetaxel for in vivo prostate cancer treatment (Farokhzad, O. C.; Cheng, J.; Teply, B. A.; Sherifi, I.; Jon, S.; Kantoff, P. W.; Richie, J. P.; Langer, R. Proc. Nat'l Acad.Sci. (USA) 2006, 103, 6315-6320), difficulties were experienced in controlling formulation parameters such as drug loading and encapsulation efficiency. The encapsulation efficiency, which depends on various parameters, including solvents, type of polymers, polymer molecular weights, and the drugs to be encapsulated, varied from batch to batch and was usually less than 80%. Drug loading was also typically lower than 10%. In many cases, only 1% of drug loading could be achieved. NPs with more than 5% of drug loading sometimes contained undesired large aggregates (>1 micron), which was presumably due to the aggregation of the non-encapsulated drug molecules. Particles with mixed sizes and wide distributions can lead to complex biodistribution and pharmacokinetic responses in vivo.
In liposome delivery systems, drug molecules are encapsulated in the core of the liposome and are, thus, separated from the external environment by lipid bi-layers which prevent leakage of encapsulated drug molecules. In contrast, polymer nanoencapsulates (polymeric nanoparticles) have no such regulating mechanism to prevent the unwanted leaking of therapeutic molecules during circulation. Significant burst release effects are one of the greatest challenges to overcome in the application of polymeric nanoparticles in vivo for drug delivery. In a vehicle with significant burst release effect, poorly encapsulated drug molecules on or near the surface of nanoparticles can quickly diffuse into solution and may lead to significant toxicity in vivo.10 Burst release is especially severe when drug loading exceeds the encapsulation threshold of the polymer where there can be a significant amount of drug molecules precipitated on the surface of the nanoparticle.
Nanoencapsulates (NE) usually display a biphasic drug release pattern10-12 with as high as 40-80% of the encapsulated drug molecules burst released during the first several or tens of hours.10 After the first 24 to 48 hours, drug release becomes significantly slower due to the increased diffusion barrier for drug molecules buried more deeply in polymer nanoparticles. When these semi- or even completely empty nanoparticles eventually arrive and accumulate at the site where they are needed (e.g., tumor tissue), they usually have little or no remaining therapeutic efficacy.6,13 
It is extremely difficult to achieve high drug loading with high encapsulation efficiency in polymeric nanoencapsulates. The encapsulation efficiency not only depends on the type, molecular weight and properties of the polymers used, but is also significantly affected by the chemical and physical properties of therapeutic molecules. For example, lower molecular weight polymers tend to exhibit lower encapsulation efficiency than higher molecular weight polymers. Hydrophilic molecules (e.g., doxorubicin) cannot be readily encapsulated into polymeric nanoparticles (Grovender T. et al. (1999) J. Controlled Release 57(2) 171-185). In all nanoencapsulates so far developed, drug loading (the weight percentage of drug in polymer nanoparticles) and encapsulation efficiency (percentage of drug encapsulated relative to total amount of drugs applied) vary dramatically from system to system and from batch to batch. For hydrophobic small molecules such as paclitaxel (Ptxl) or docetaxel (Dtxl), it is common that nanoparticle loading is in a range of 1 to 5 wt % and encapsulation efficiency varies from ˜20- to 80%.10,14 
Another problem encountered in nanoparticle drug encapsulation is undesirable particle heterogeneity. Nanoprecipitation of polymer and drugs, such as chemotherapeutics, frequently gives multimodal distributions as measured by dynamic light scattering, ranging from ˜100 nm to 1 μm or higher. Particle heterogeneity may result because encapsulation involves distinct chemical species, a polymer and a drug molecule, with distinct molecular weights, flexibility and rigidity, hydrophobicity and tendencies toward forming crystals. Therefore it is likely the polymer and the drug molecule would tend to self-aggregate during nanoprecipitation leading to particle heterogeneity.
Nanoparticle materials exhibiting multimodal distributions are usually treated as having a different degree of aggregation of small nanoparticles with identical composition. However, this assumption may not always be correct. In a recent investigation on the effect of docetaxel loading at 1%, 5% and 10% on resulting PEG-b-PLGA nanoparticle size distributions (Cheng, J. et al. Formulation of functionalized PLGA-PEG nanoparticles for in vivo targeted drug delivery. Biomaterials 28, 869-76 (2007)), polydispersity of the particle preparations increased with docetaxel concentration from 0.154 for 1% loading to 0.203 for 5% loading and 0.212 for 10% loading. The size distribution of the nanoparticles exhibited a biphasic trend with a smaller diameter particle distribution accompanied by a distribution of larger diameter particles. The distribution corresponding to the smaller particles did not shift with the increase of drug concentration. The larger diameter locus of the two size distributions shifted higher as the drug loading increased (the size increasing from ˜300 nm to ˜1200 nm). Since the only difference between these formulations is the amount of drug loading, a significant amount of the nanoparticles formed may be due to aggregation of unencapsulated docetaxel due to its poor water solubility. In this work and that of others (Avgoustakis, K. et al. PLGA-mPEG nanoparticles of cisplatin: in vitro nanoparticle degradation, in vitro drug release and in vivo drug residence in blood properties. J. Controlled Release 79, 123-135 (2002)) on nanoprecipitation using polylactide and docetaxel, biphasic particle distributions were almost always observed.
It is desirable to develop a methodology to circumvent these difficulties, which will provide NPs with batch-to-batch consistency in encapsulation efficiency and drug loading. This invention provides a simple, one-step strategy for the preparation of drug-polymer (and drug-oligomer) conjugates which can be formed into nanoparticles with 100% encapsulation efficiency and predetermined drug loading. The nanoparticles formed by the methods herein employing drug conjugates are call nanoconjugates herein to distinguish over nanoencapsulates (NE). Further, the method of this invention can be broadly applied to provide polymer and oligomer conjugates of a variety of useful chemical species (bioactive species, drugs, reagents, diagnostics, contrast agents, reporter molecules, dyes, etc.) for the preparation of particulate delivery systems.